Systemic immunotoxin treatment inhibits formation of human breast cancer metastasis and tumor growth in nude rats

Int J Cancer. 2000 Dec 15;88(6):970-6. doi: 10.1002/1097-0215(20001215)88:6<970::aid-ijc21>3.0.co;2-q.

Abstract

Adjuvant chemotherapy in breast cancer patients has had limited success, which is possibly because of lack of effect on non-proliferating cells accompanied by the emergence of drug-resistant cell clones. Since immunotoxins (ITs) are known to exert proliferation-independent cytotoxicity, we investigated the efficacy of systemically administered anti-carcinoma ITs in nude rat models, simulating micrometastatic disease. The monoclonal antibodies MOC31, BM7 and 425.3, which recognize epithelial glycoprotein 2, MUC-1 mucin and the epidermal growth factor receptor, chemically conjugated to Pseudomonas exotoxin A (PE), inhibited protein synthesis of the 2 breast cancer cell lines at concentrations of 0.3-0.4 ng/ml, except for BM7-PE, which was less efficacious (65 ng/ml). In the MA-11 model in nude rats, a single i. v. dose of 20 microg MOC31-PE prevented development of metastasis in the spinal cord in 11/19 (58%) of the animals. Similarly, 425.3-PE treatment gave 6/9 (66%) long-term survivors. In rats injected intracardially or intratibially with MT-1 cells, treatment with 425. 3-PE prevented metastasis in 4/10 (40%) and intratibial tumor growth in 17/18 (94%) of the rats. Importantly, an equimolar dose of free 425.3 (antibody) was ineffective, whereas PE alone was toxic. With BM7-PE, 5/17 (29%) cures were obtained in the intratibial model. The results demonstrate that systemic short-term treatment with non-toxic doses of the 3 ITs tested can effectively inhibit the development of experimental breast cancer metastasis and/or local tumor growth in bone. The results support the development of the ITs towards clinical evaluation for possible use as short-term adjuvant therapy in patients at high risk of early relapse.

MeSH terms

  • ADP Ribose Transferases*
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents / therapeutic use
  • Bacterial Toxins*
  • Bone Neoplasms / prevention & control
  • Bone Neoplasms / secondary
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Cisplatin / therapeutic use
  • Doxorubicin / therapeutic use
  • ErbB Receptors / immunology*
  • Exotoxins / therapeutic use*
  • Female
  • Immunotoxins / therapeutic use*
  • Injections, Intravenous
  • Male
  • Rats
  • Rats, Nude
  • Specific Pathogen-Free Organisms
  • Spinal Neoplasms / prevention & control
  • Spinal Neoplasms / secondary
  • Tibia
  • Tumor Cells, Cultured
  • Virulence Factors*

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Bacterial Toxins
  • Exotoxins
  • Immunotoxins
  • Virulence Factors
  • Doxorubicin
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa
  • ErbB Receptors
  • Cisplatin